Gene therapy generally relates to the delivery of one or more heterologous genes to a subject in order to treat a disease. Hemophilia is a genetic disease caused by a deficiency of a blood clotting factor. There are two types of X-linked bleeding disorders, hemophilia A and hemophilia B. In some cases of von Willebrand disease, the most common bleeding disorder, deficient levels of vWF result in low levels of factor VIII, mimicking hemophilia A. Hemophilia A affects about 17,000 people in the US and is caused by a deficiency in factor VIII. The incidence of hemophilia B is 1 out of 34,500 men, and it is caused by a deficiency in factor IX. Each of these diseases is an excellent theoretical candidate for gene therapy, as each has a reasonably simple molecular pathology and should be remediable by the delivery of a single gene.
Successful gene therapy for hemophilia requires both tissue specific expression, to avoid a counterproductive immune response, and sufficiently high levels of expression to generate a therapeutic response. Gene therapy directed at quiescent cells of the liver presents an additional challenge, as Park et al. teach that stable and efficient transduction of liver cells with a lentiviral vector requires cell proliferation (Park et al., 2000, Nature Genetics 24:49–52). Park et al. further teach that the injection of doses of the lentiviral vector sufficiently high to reach therapeutic levels of transgene expression in the liver produces a very high liver toxicity and a high mortality (Park et al., 2000, Blood 96(3):1173–1176).
There remains a need for successful gene therapy of quiescent cells that results in therapeutically acceptable cell transduction and that produces a therapeutic amount of protein without toxicity. There is a particular need for a safe and efficient gene therapy for hemophilia.